Despite the increasing numbers of aging individuals in our country, there is little understanding of the interaction between the mechanisms of aging and the pathophysiology of age-related diseases. Research in this area is essential since age is the largest risk factor for various diseases. If this relationship can be resolved, it would open new avenues for therapeutic interventions to treat/prevent age-related diseases. Oxidative stress is one of the fundamental biological processes that link aging and age-related diseases. Yet, studies using transgenic/knockout mice with various antioxidant enzyme levels have yielded contradictory results. My laboratory has pursued novel animal models and innovative approaches to examine mechanisms by which oxidative stress plays a role in aging and age-related diseases. For this purpose, we conducted a study with genetically-modified Sprague-Dawley (SD) rats that globally overexpress Cu/ZnSOD [Tg(hSOD1)+/0]. Notably, Tg(hSOD1)+/0 SD rats had a significant increase in lifespan and a major reduction in age-related pathologies. Moreover, while aged wild-type (WT) rats became obese and insulin resistant (a classic feature of aged WT SD rats), Tg(hSOD1)+/0 SD rats had lower plasma glucose and insulin concentrations, and increased insulin sensitivity as measured with an insulin clamp. These results were the first to show that overexpressing Cu/ZnSOD had beneficial effects on aging and age-related diseases in rats, and our findings suggest that the benefits of Cu/ZnSOD overexpression on age-related pathology may be mediated, in part, through pathways that regulate glucose metabolism. To advance these seminal findings, the goal of the current application is to assess the specific mechanisms contributing to the improved lifespan and healthspan of Tg(hSOD1)+/0 SD rats. We propose that Cu/ZnSOD overexpression increases longevity in SD rats by attenuating age-related metabolic disorders that underlie age-related pathophysiology. The increase in adiposity and accompanying secretory phenotypic changes are considered to play major roles in aging and the onset/progression of various age-related diseases through several mechanisms, e.g., systemic inflammation, insulin insensitivity, oxidative stress, and redox-sensitive signaling changes. Importantly, we found that Cu/ZnSOD overexpression significantly reduced the accumulation of senescent cells in adipose tissue, and enhanced the insulin signaling pathway mainly in skeletal muscle. Here, we hypothesize that Cu/ZnSOD overexpression in SD rats improves age-related changes in metabolic health by 1) attenuating secretory phenotypic changes in fat tissues and/or 2) enhancing insulin sensitivity in skeletal muscles. To further examine the possible underlying mechanisms involved in age-related changes in metabolic health, we recently generated two novel SD rat models: 1) overexpressing Cu/ZnSOD only in skeletal muscle [Tg(MCK-hSOD1)+/0]; and 2) overexpressing Cu/ZnSOD only in adipose tissue [Tg(ADN-hSOD1)+/0]. The Tg(MCK-hSOD1)+/0 (skeletal muscle) SD rats were developed because skeletal muscle is the predominant site for insulin-mediated glucose disposal and oxidation; while the Tg(ADN-hSOD1)+/0 (adipose tissue) SD rats will allow us to examine how cellular senescence and secretory phenotypic changes in adipose tissue contribute to insulin resistance and age-related pathology. If successful, the study will elucidate the role of oxidative stress pathways in the genesis of age-related metabolic disorders. This work will be the first to directly determine whether effects of enhanced antioxidant protection in skeletal muscle and/or adipose tissue could prevent insulin resistance, either by altering age-related changes in the secretory phenotype of adipose tissue, and/or insulin action of skeletal muscle in our unique rat models. This is a novel approach, which could provide critical information in identifying the cellular basis for age-related metabolic disorders in obese individuals, many of whom have an increased risk of insulin resistance, diabetes, cancer, and cardiovascular disease. Thus, this work could have a significant impact on public health for many chronic diseases affecting the U.S. population, each of which is exacerbated by age-related changes in metabolic health under an obese condition.